The “stress urinary incontinence” is a disease characterized by a symptom of urine leakage when the abdominal pressure temporarily increases upon coughing, sneezing, straining or during light exercise such as going up and down the stairs and the like, or holding up a heavy luggage and the like, which is a disorder in the urinary continence mechanism. This disease is very common in women, and considered to occur because the pelvic floor muscles become weak due to birth and aging, and anatomical positions of pelvic organs including the bladder and urethra change (see, for example, “The Journal of Family Practice”, 1982, vol. 14, p. 935-936). When the intravesical pressure increases due to an abrupt increase in the abdominal pressure, it is considered that the abdominal pressure passively transmits to the bladder and urethra, as well as the pelvic floor muscles and external urethral sphincter muscle actively contract via the nerve system to maintain urinary continence (see, for example, “The Journal of Urology”, 1982, vol. 127, p. 1202-1206). Weakening of the pelvic floor muscles and external urethral sphincter muscle due to birth and aging is considered to be one cause of stress urinary incontinence, and it has been reported that the patients with stress urinary incontinence possibly have a defects in the reflex urinary continence mechanisms (see, for example, “British Journal of Urology”, 1994, vol. 73, p. 413-417).
In mammals inclusive of human, when the urinary continence mechanism is intact, urine leakage due to an increase in the intravesical pressure associated with an abrupt increase in the abdominal pressure can be avoided by the function of the competing reflex increase in the intraurethral pressure. On the other hand, when, for example, a defect is present in a part of the urinary continence mechanism, for example, a defect in the neural systems involved in the guarding reflexs and a decrease in the contractile force of muscles involved in intraurethral pressure increase and the like, reflex increase in the intraurethral pressure cannot resist an increase in the intravesical pressure caused by an abrupt increase in the abdominal pressure, and urine leakage occurs. For screening for a therapeutic drug for stress urinary incontinence, therefore, an evaluation system reflecting such pathology is important.
Since many of human patients with stress urinary incontinence are parous women, and the frequency thereof increases in the postmenopausal period, external injury due to the delivery and decreased female hormone are held responsible therefore. As the situation stands, model rats are prepared using female rats as animals and based on vaginal expansion of parous rats and virgin rats, ovary removal, or combination of these (see, for example, “Urology”, 1998, vol. 52, p. 143-151, and “The Journal of Urology”, 2001, vol. 166, p. 311-317). As an evaluation parameter for the clinical diagnosis of stress urinary incontinence, the leak point pressure showing the urethral resistance in the urinary storage period is used. In animal experiment, it is a general method to gradually inject saline into the bladder under conditions free of the reflex voiding and measure the intravesical pressure at the time point of saline leakage from the uretral orifice (modified leak point pressure), or electrostimulate the abdominal wall or induce a sneeze by stimulating the mucous surface of the nasal cavity with a whisker when a half volume of the bladder is filled to increase the intravesical pressure, and observe the presence or absence of urine leakage (see, for example, “Urology”, 1998, vol. 52, p. 143-151, and “The Journal of Urology”, 2001, vol. 166, p. 311-317). However, in the former measurement, the increase in the intravesical pressure is persistent and gradual, and therefore, is not entirely considered to reflect the abrupt increase in the intravesical pressure that induces stress urinary incontinence. In the latter measurement, merely the presence or absence of stress urinary incontinence is detected, and the measurement is not entirely considered to quantitatively show the level of pathology. While a method including inducing a sneeze in anesthetized rats and measuring the sneeze leak point pressure at that time has also been reported (see, for example, “American Journal of Physiology-Regulatory, Integrative and Comparative Physiology”, 2003, vol. 285, p. R356-R3656), the degree of increase in the intravesical pressure depends on the size of sneeze, which is difficult to control. A report has documented that an anesthetized dog is made to sneeze and the intraurethral pressure and the like are measured for the purpose of examining the mechanism of urinary continence maintenance (see, for example, “The Journal of Urology”, 1982, vol. 127, p. 1202-1206, and “Urologia internationalis”, 1987, vol. 42, p. 195-200). In these reports, however, changes in the topical pressure in a portion of urethra are measured, and the resistance of the whole urethra during increase in the abdominal pressure is not evaluated.
In addition, a method including electrostimulating an animal and measuring only the presence or absence of urine leakage has been reported (see “International Urogynecology Journal”, 2001, vol. 12, p 170-177).
In small mammals, moreover, a screening method for a drug for the prophylaxis or treatment of stress urinary incontinence, which comprises measuring reflex contractile force of the pelvic floor muscles based on the intraurethral pressure has been reported (see JP-A-2004-159919).
There are many known compounds that bind to a serotonin 5-HT2C eceptor. WO02/040457, WO02/083863, WO03/097636, WO04/000829, WO04/000830, and WO02/008178 describe that a compound that bind to a serotonin 5-HT2C receptor is useful for the treatment of urinary incontinence and the like. However, they do not describe a treatment effect on the stress urinary incontinence.
WO99/20279 describes that a serotonin uptake inhibitor is useful for the treatment of urinary incontinence.
JP-A-7-188003 describes that duloxetine, which is a serotonin uptake inhibitor, is useful for the treatment of urgency incontinence and stress incontinence.